2-amino-alpha-substituted-benzylamines



s,2ss,52s 2-AMIN-wSUBSTETUTED-BENZYLAMHNES Staniey C. Bell and Scott J. Childress, Philadelphia, Pa, assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Jan. 20, 1964, Ser. No. 338,598 3 Claims. (Cl. 260-2475) Examination of the compounds produced according to the hereinafter described processes reveals data confirming the molecular structure hereinbefore set forth. For example, the exocyclic NH frequency is evident in the infrared spectrum of the compounds.

The tangible embodiments of the invention possess the inherent applied use characteristic of exerting qualitatively varying therapeutic effects in experimental animals as evidenced by pharmacological evaluation according to standard test procedure. These tangible embodiments show anticonvulsant, anti-parkinsonian and central nervous system activities.

The manner and process of making the invention will now be described so as to enable a person skilled in the art of chemistry to make and use the same.

The starting Z-arnino-u-substituted-benzylideneamines can be prepared as disclosed and claimed in copending application Ser. No. 297,705, filed July 25, 1963.

The preparative aspect of this invention is illustrated schematically for a specific embodiment in Scheme A, below, and more generally in Scheme B, to which the numerals in parentheses in the following description refer.

It has been found that upon treating either the 06- or the B-form of N-[2 (2 amino-ot-phenylbenzylideneamino) ethyl]morpholine (1) with a reducing agent there is formed the corresponding compound, N-[2-(2-amino-otphenylbenzylamino)ethyl]morpholine (2), in which the exocyclic C=N linkage has been reduced.

United States Patent A preferred technique for eifecting the above-outlined reaction is to add an aqueous solution of sodium borohydride to a mixture of the benzylidene compound and a solvent therefor such as Water, benzene, alcohol or triethanolamine. The reaction mixture is then heated to 50 to 60 C., cooled, acidified with an organic acid such as acetic acid, and then made basic with a strong base such as sodium hydroxide. The product is then recovered by conventional methods. The above reaction can be carried out with various reducing agents including potassium borohydride, lithium aluminum hydride, as well as by catalytic hydrogenation.

It will be apparent from the disclosure herein to those skilled in the art of organic chemistry that for the purposes of this invention certain of the carbon atoms of the starting benzylideneamine (l) (3) can be substituted with inert groups which do not interfere with the reduction of the exocyclic C=N bond. Therefore, in the process of the invention, except for limitations expressed herein, all Z-amino-a-substituted benzylideneamines can be used as starting materials in the process of making aspect of the invention. Thus, the benzenoid moiety of the starting compound can be substituted on any available position on the ring by one or more non-interfering substituents such as straight chain or branched lower alkyls having up to 9 carbon atoms in the chain, chlorine, bromine or fluorine, halo(lower)alkyl, for example, but without limitation, dichloromethyl and trifiuoromethyl, and nitro. However, where the starting material is catalytically hydrogenated any nitro group thereon will be reduced to an amino group. Similarly, one or both of the hydrogens on the Z-amino group starting compound may be replaced by a substituent (Scheme B, A and B) such as for example, but without limitation, (lower)alkyl, i.e., methyl, ethyl, propyl, pentyl and hexyl, and aralkyl such as, for example, but without limitation, benzyl and phenethyl, lower alkanoyl, such as, for example, but without limitation, acetyl or halo(lower) alkanoyl such as chloroacetyl. However, it should be noted that where lithium aluminum hydride is employed as the reducing agent it will also reduce the aforementioned acyl substituents. The starting products can also have on the exocyclic carbon a substituent (Scheme B, W) other than phenyl, such as, for example, but without limitation, a (lowerlalkyl group as hereinbefore defined, an alicyclic group such as cyclo hexyl, or a 2-furyl, or 2- or 3-thienyl. Such compounds and those where W is phenyl substituted by any of the substituents present on the benzenoid moiety of the claimed structure are full equivalents of the subject matter particularly claimed.

It will be apparent to those skilled in the art that the above-described reduction is not materially affected by the chain length of the alkylene group which is attached to the exocyclic nitrogen. Indeed said group can have from one to five or more carbon atoms therein and can have on its omega position various substituent groups (Scheme B, Z) such as amino and substituted amino such as alkylamino, including methylamino, ethylamino, and propylamino; dialkylamino, including dimethylamino, diethylamino, dipropylamino; and heterocyclic amino, including pyrrolidino and piperidino. Such variations in the molecular structure of the composition aspects as hereinbefore described are considered as equivalents of the subject matter sought to be patented.

It will also be appreciated by those skilled in the art of organic chemistry that alternative methods of producing the desired 2-amino-wsubstituted benzylamines can be employed. Thus, a substituted Z-amino-wphenylbenzyl halide may readily be reacted with the appropriate amine to form compounds encompassed by the principal composition aspect of this invention.

The best mode contemplated by the inventors for carrying out their invention will now be set forth as follows:

EXAMPLE 1 Preparation of N-[2--(Z-amino-5-ehloro-a-phenylbenzylamino)ethyllmorpholine Add a solution of 1.0 g. of sodium borohydride in 25 ml. of Water to a suspension of 3.0 g. of the a-form of N-[2-(2 amino-S-chloro-u-phenylbenzylideneamino)ethyl]morpholine in 50 m1. of ethanol and heat the reaction mixture at 5060 for 20 minutes. carefully acidify With acetic acid, dilute with Water and make basic with sodium hydroxide. Extract the product With ether and then from the ether with a dilute hydrochloric acid solution. Make alkaline and extract with ether. Evaporate the ether to give N-[2-(2-amino-5- chloro-a-phenylbenzylamino)ethyl] morpholine, which is isolated from ethanol as the trihydrochloride salt, M.P. 185-187, or as the dihydrochloride salt, M.P. 199-201 The following example illustrates an alternative method for preparing the compositions of the invention.

EXAMPLE 2 Reduce a solution of 2.0 g. of N-[Z-(Z-amino-S-chloroa-phenylbenzylideneamino)ethyl]morpholine in 100 m1. of ethanol With 5% platinum on alumina until one Cool the solution,

equivalent of hydrogen is consumed. Filter the alcohol solution from the catalyst and bubble gaseous hydrogen chloride into the alcohol solution to obtain N-[2-(2- amino-5 chloro-a-phenylbenzylamino)ethyl]morpholine trihydrochloride.

It is apparent to a chemist skilled in the art that our novel compounds are basic in nature and will form acid salts with a number of organic and inorganic acids including, for example, but Without limitation, hydrochloric, sulfuric, acetic and succinic acids.

The composition of this invention may be administered parenterally or orally and may be combined with diluents, solvents, suspending agents, fillers, excipients, adhesives, coloring and flavoring agents as desired for the preparation of convenient dosage forms.

What is claimed is:

l. N-[2-(2 amino-S-chloro-a-phenylbenzylamino)ethyl]morpholine.

2. The dihydrochloride salt of N-[Z-(Z-amino-S-chloroot-phenylbenzylamino) ethyl] morpholine.

3. The trihydrochloride salt of N-[2-(2-amino-5-chloroot-phenylbenzylamino) ethyl] morpholine.

No references cited.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

R. J. GALLAGHER, Assistant Examiner. 

1. N-(2-(-AMINO-5-CHLORO-A-PHENYLBENZYLAMINO)ETHYL)MORPHOLINE. 